WO2007141200A1 - Nouveaux dérivés de pyridinone substituée par n-aryle et n-hétéroaryle en vue d'une utilisation dans des maladies à médiation par mch-1 - Google Patents

Nouveaux dérivés de pyridinone substituée par n-aryle et n-hétéroaryle en vue d'une utilisation dans des maladies à médiation par mch-1 Download PDF

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WO2007141200A1
WO2007141200A1 PCT/EP2007/055376 EP2007055376W WO2007141200A1 WO 2007141200 A1 WO2007141200 A1 WO 2007141200A1 EP 2007055376 W EP2007055376 W EP 2007055376W WO 2007141200 A1 WO2007141200 A1 WO 2007141200A1
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group
alkyl
compound according
disorders
compound
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PCT/EP2007/055376
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WO2007141200A8 (fr
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Manuel Jesús ALCÁZAR-VACA
José Ignacio ANDRÉS-GIL
Frank Matthias Dautzenberg
Jacqueline Macritchie
Julen Oyarzabal Santamarina
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Janssen Pharmaceutica N.V.
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Publication of WO2007141200A1 publication Critical patent/WO2007141200A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention concerns N-aryl and N-heteroaryl substituted pyridinone derivatives having antagonistic melanin-concentrating hormone (MCH) activity, in particular MCH-I activity. It further relates to their preparation, compositions comprising them and their use as a medicine.
  • MCH melanin-concentrating hormone
  • MCH Melanin concentrating hormone
  • C ⁇ S central nervous system
  • MCH-I and MCH-2 G protein-coupled receptors
  • MCH-I receptor was considered a valuable target for the treatment of obesity as MCH promotes feeding behaviour in rodents (Nature (1996), 380, 243-247). Recently however, it was shown that MCH-I antagonism pro- prises anxiolytic and antidepressant profiles in rodents (Nat. Med. (2002) 8, 825-830; Neuropharmacology (2004), 46, 457-467 ; Neuropsychopharmacology (2005), in press). Thus, it is currently generally accepted that MCH receptors, particularly the MCH-I receptor, are a good target for the treatment of affective spectrum disorders (Eur. J. Neuroscience (2000) 12, 1194-1216).
  • MCH-I receptor mRNA and protein are distributed in various hypothalamic nuclei including the paraventricular nucleus and several limbic structures all implicated in the regulation of emotion and stress (Eur. J. Neuroscience (2000) 12, 1194-1216). In addition, dense labelling is detected in the nucleus accumbens shell (J. Comp. Neurol. (2001) 435, 26-40). Injection of MCH directly into the paraventricular nucleus has been found to increase plasma adrenocorticotropic hormone (ACTH) and to alter sleep architecture (Verret et al. 2003, BMC Neurosci 4:19).
  • ACTH plasma adrenocorticotropic hormone
  • MCH corticotro- phin-releasing factor
  • CRF corticotro- phin-releasing factor
  • MCH-I antagonist SNAP-7941
  • antidepressant- and axiolytic-like affects in rodents tests, supporting a role for MCH-I re- ceptor in depression and anxiety.
  • MCH-I antagonists A large number of companies is now actively pursuing the development of MCH-I antagonists and a wide range of structural types have been reported in a num- ber of patent publications, mostly in relation to the regulation of food intake and energy expenditure (Expert Opin. Ther. Patents (2005) 15(10)). The majority of reported MCH-antagonists incorporate a basic centre and two (hetero)aromatic parts, joined by linkers.
  • WO 2005/085200 (Banyu Pharmaceutical Co., Ltd) discloses pyridinone, pyrimidinone and pyridazinone-derivatives for use as MCH-I antagonists.
  • WO 2003/033480, WO 2003/033476 and WO 2005/05042541 disclose different bicyclic heterocycles, such as thieno- pyrimid-4-one-, benzopyrimid-4-one- and ftalimide-derivatives, for use as MCH-I antagonists.
  • WO 2003/097047 and WO 2005/040157 (Eli Lilly and Company) and WO 2005/070925 (Aventis Pharma GmbH) report different aromatic 5-membered ring heterocycles, such as oxazole- and oxadiazole-derivatives, for use as MCH-I antagonists.
  • WO 2004/011438 and WO 2005/070898 (Aventis Pharma GmbH GMBH) disclose diaryl-substituted cyclic urea derivatives as MCH-I antagonist.
  • WO 2003/068230 (Pharmacia Corporation) discloses the preparation of substituted pyridinones as modulators of p38 MAP kinase.
  • MCH melanin-concentrating
  • a pharmaceutically acceptable acid or base addition salt thereof an TV-oxide form thereof or a quaternary ammonium salt thereof, wherein A is phenyl or pyridinyl ;
  • R 1 , R 2 are each, independently from each other, selected from the group of hydrogen, Ci- 3 alkyl, aryl,; arylC 1 . 3 alky 1, Het, HetC 1-3 alkyl,
  • R 1 and R 2 are taken together to form an TV-containing heterocycle, selected from the group of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl ; wherein each of the afore- mentioned TV-containing heterocycles are optionally substituted by k substitu- ents R 3 ;
  • R 3 is selected from the group of hydrogen, halo, cyano, hydroxy, NR a R b , oxo, carboxyl, aminocarbonyl, nitro, thio, formyl, C 1-3 alkyl, aryl, and R a , R b are each, independently from each other, selected from the group of hydrogen, C 1-3 alkyl, aryl, Het, sulphonyl, and ; or R a and R b are taken together to form an TV-containing heterocycle, selected from the group of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, l-aza-bicyclo[2.2.1]heptyl, and thiomorpholinyl ;
  • R 4 , R 5 are each, independently from each other, selected from the group of hydrogen, halo, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C 1-3 alkyl, and k is an integer, equal to zero, 1, 2, 3 or 4 ; 1 is an integer, equal to zero, 1, 2, 3 or 4 ; m is an integer, equal to zero, 1 , 2 or 3 ;
  • Y 1 , Y 3 are each, independently from each other, selected from the group of a single bond, O, NR 7 , S, SO, and SO 2 ; wherein R 7 is selected from the group of hydrogen and ; Y 2 is a saturated or unsaturated, straight or branched Ci- 6 -hydrocarbon radical, wherein one or more hydrogen atoms may optionally be replaced by a radical selected from the group of halo, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, and formyl ;
  • B is a 6-membered ring containing zero, 1, 2 or 3 nitrogen atoms, optionally substituted with p substituents R 6 , each independently from each other, selected from the group of hydrogen, halo, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl, C 1-3 alkyl, and C 1-3 alkyloxy ; and wherein p is an integer, equal to zero, 1 or 2 ; or two substituents R 6 may be combined into a radical -CH 2 CH 2 CH 2 - or -OCH 2 O- ; alkyl is a straight or branched saturated hydrocarbon radical having the indicated number of carbon atoms ; wherein the radical may optionally be substituted on one or more carbon atoms with one or more radicals selected from the group of halo, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl ; aryl is naphthyl or pheny
  • Het is a heterocyclic radical selected from the group of pyrrolidinyl, imida-zolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolinyl, imidazolinyl, pyrrazolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, azepyl, diazepyl, morpholinyl, thiomorpholinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, dioxolyl, dithianyl, tetrahydrofuryl, tetrahydro- pyranyl, and oxadiazolyl ; where
  • compounds according to the invention is meant a compound according to the general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an TV-oxide form thereof or a quaternary ammonium salt thereof, including the above compounds disclosed in WO 2003/068230. Only for establishing the compound scope, it is understood that these compounds are disclaimed by way of a disclaimer.
  • the invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an TV-oxide form thereof, or a quaternary ammonium salt thereof.
  • the invention also relates to the use of a compound according to the invention as a medicament and for the preparation of a medicament for the prevention and/or treatment of a disorder or disease responsive to antagonism of the MCH receptor, in particular to antagonism of the MCH-I receptor.
  • the invention relates to the use of a compound according to the in- vention for the preparation of a medicament for the prevention and/or treatment of psychiatric disorders, including but not limited to anxiety, eating disorders, mood disorders, such as bipolar disorders and depression, psychoses, such as schizophrenia, and sleeping disorders. Additionally, the compound can be used for treating obesity, diabetes, sexual disorders and neurological disorders.
  • a compound according to the invention, in particular according to Formula (I), may also be suitable as add-on treatment or combination treatment and/or prophylaxis in the above listed diseases, in particular for the prevention and/or treatment of psychiatric disorders, in combination with antidepressants, anxiolytics and/or antipsychotics which are currently available or in development or which will become available in the future, in particular to improve efficacy and/or onset of action.
  • antidepressants anxiolytics and/or antipsychotics
  • antipsychotics which are currently available or in development or which will become available in the future, in particular to improve efficacy and/or onset of action.
  • antidepressants anxiolytics and/or antipsychotics
  • compounds are evaluated in combination with antidepressants, anxiolytics and/or antipsychotics for attenuation of stress-induced hyperthermia.
  • the invention therefore also relates to the use of the compounds according to the invention in combination with one or more other compounds selected from the group of antidepressants, anxiolytics and antipsychotics, to a pharmaceutical composition comprising the compounds according to the invention and one or more other compounds selected from the group of antidepressants, anxiolytics and antipsychotics, as well as to a process for the preparation of such pharmaceutical compositions.
  • the invention also relates to the use of the compounds according to the invention in combination with one or more other compounds selected from the group of lipid- lowering compounds for the prevention and/or treatment of obesity, to a pharmaceutical composition comprising the compounds according to the invention and one or more other compounds selected from the group of lipid-lowering compounds, as well as to a process for the preparation of such pharmaceutical compositions.
  • the invention relates to a compound according to the invention, wherein each of R 1 , R 2 , independently from each other, is selected from the group of hydrogen, C 1-3 alkyl, arylC 1 . 3 alky 1, HetC 1-3 alkyl, and NR a R b Ci- 3 alkyl.
  • the is substituted with hydroxy or amino .
  • the invention relates to a compound according to the invention, wherein R 1 and R 2 are taken together to form an TV-containing heterocycle, selected from the group of pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thio- morpholinyl ; and wherein each of the foregoing TV-containing heterocycles is option- ally substituted by k substituents R 3 .
  • the invention relates to a compound according to the invention, wherein R 3 is selected from the group of hydroxy, NR a R b , aminocarbonyl, C 1-3 alkyl, aryl, and
  • the invention relates to a compound according to the invention, wherein R a , R b are each, independently from each other, selected from the group of hydrogen, C 1-3 alkyl, C 1-3 alkylcarbonyl. C 1-3 alkyloxycarbonyl, and C 1-3 alkyl- sulphonyl; or R a and R b are taken together to form an N-containing heterocycle, selected from the group of pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, l-aza-bicyclo[2.2.1]heptyl, and thiomorpholinyl.
  • the invention relates to a compound according to the invention, wherein A is phenyl.
  • the invention relates to a compound according to the invention, wherein each of R 4 and R 5 , independently from each other, are selected from the group of hydrogen, halo, C 1-3 alkyl, and
  • the invention relates to a compound according to the in- vention, wherein k is 1.
  • the invention relates to a compound according to the invention, wherein 1 is zero.
  • the invention relates to a compound according to the invention, wherein m is zero. In another embodiment, the invention relates to a compound according to the invention, wherein Y 1 and Y 3 are each, independently from each other, selected from the group of a single bond and O.
  • the invention relates to a compound according to the invention, wherein Y 2 is selected from the group of saturated or unsaturated, straight or branched C 1-6 hydrocarbon radicals.
  • the invention relates to a compound according to the invention, wherein B is selected from the group of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • B is phenyl, pyridinyl or pyridazinyl. More preferably, B is phenyl.
  • the invention relates to a compound according to the invention, wherein the moiety B-Y'-Y ⁇ Y 3 is selected from the radicals (a-1) to (d-5) as listed below, optionally substituted with p substituents R 6 , each independently from each other, selected from the group of hydrogen, fluoro, chloro, hydroxy, methyl, trifluoromethyl, fiuoromethyloxy, difiuoromethyloxy, and methyloxy ; and wherein p is an integer, equal to zero, 1 or 2 ; or two substituents R 6 are combined into a radical -CH 2 CH 2 CH 2 - or -OCH 2 O-.
  • the moiety B-Y'-Y 2 ⁇ 3 is selected from the radicals (a-1), (a-2), (a-3) and (b-3).
  • alkyl is a straight or branched saturated hydrocarbon radical having the indicated number of carbon atoms, i.e. when is indicated, the alkyl radical may contain from 1 to 3 carbon atom ; and when is indicated, the alkyl radical may contain from 1 to 6 carbon atom.
  • Each radical may optionally be substituted on one or more carbon atoms with one or more radicals selected from the group of halo, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio and formyl.
  • alkyl is methyl, ethyl, propyl or isopropyl. Further radicals that are embraced within the scope are e.g.
  • aryl is naphthyl or phenyl, each optionally substituted with 1, 2 or 3 substituents, each independently from each other, selected from the group of halo, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl and
  • substituents each independently from each other, selected from the group of halo, cyano, hydroxy, amino, oxo, carboxyl, nitro, thio, formyl
  • halo is a substituent selected from the group of fluoro, chloro, bromo and iodo.
  • halo is fluoro, chloro or bromo.
  • a bond can be any bond, including a covalent bond, a single bond, a double bond, a triple bond, a coordination bond and a hydrogen bond.
  • a pharmaceutically acceptable acid addition salt is defined to comprise a therapeutically active non-toxic acid addition salt form that a compound according to Formula (I) is able to form.
  • Said salt can be obtained by treating the base form of a compound according to Formula (I) with an appropriate acid, for example an inorganic acid, for example hydrohalic acid, in particular hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid ; an organic acid, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-amino salicylic acid and pamoic acid
  • the compound according to Formula (I) containing an acidic proton may also be converted into a therapeutically active non-toxic metal or amine addition salt form
  • Ap- intestinal base salt forms comprise, for example, the ammonium salts, the alkaline and earth alkaline metal salts, in particular lithium, sodium, potassium, magnesium and cal- cium salts, salts with organic bases, e.g. the benzathine, TV-methyl-D-glucamine, hy- bramine salts, and salts with amino acids, for example arginine and lysine.
  • salt form can be converted into the free form by treatment with an appropriate acid.
  • addition salt as used in the framework of this application also comprises a solvate that the compound according to Formula (I), as well as a salt thereof, is able to form.
  • solvates are, for example, hydrates and alcoholates.
  • the TV-oxide form of the compound according to Formula (I) is meant to comprise a compound of Formula (I) wherein one or several nitrogen atoms are oxidized to so-called TV-oxides, particularly those TV-oxides wherein one or more tertiary nitrogens (e.g. of the piperazinyl or piperidinyl radical) are TV-oxidized.
  • TV-oxides can easily be obtained by a skilled person without any inventive skills and they are obvious alternatives for a compound according to Formula (I) since these compounds are metabolites, which are formed by oxidation in the human body upon uptake .
  • oxidation is normally the first step involved in drug metabolism (Textbook of Organic Medicinal and Pharmaceutical Chemistry, 1977, pages 70- 75).
  • the metabolite form of a compound can also be administered to a human instead of the compound per se, with much the same effects.
  • a compound of Formula (I) may be converted to the corresponding TV-oxide form following art-known procedures for converting a trivalent nitrogen into its TV-oxide form.
  • Said TV-oxidation reaction may generally be carried out by reacting the compound of Formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate or- ganic peroxides may comprise peroxy acids such as, for example, benzenecarboper- oxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • 3-chlorobenzenecarbo- peroxoic acid peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide.
  • Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • a quaternary ammonium salt of compound according to Formula (I) defines said compound which is able to form by a reaction between a basic nitrogen of a com- pound according to Formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, in particular methyliodide and benzyliodide.
  • an appropriate quaternizing agent such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, in particular methyliodide and benzyliodide.
  • Other reactants with good leaving groups may also be used, such as, for example, alkyl trifluoromethanesulfonates, alkyl methanesulfonates and alkyl p-toluenesulfonates.
  • a quaternary ammonium salt has at least one positively charged nitrogen.
  • the invention also comprises a derivative compound (usually called "pro-drug") of a pharmacologically-active compound according to the invention, in particular ac- cording to Formula (I), which is degraded in vivo to yield a compound according to the invention.
  • Pro-drugs are usually (but not always) of lower potency at the target receptor than the compounds to which they are degraded.
  • Pro-drugs are particularly useful when the desired compound has chemical or physical properties that make its administration difficult or inefficient. For example, the desired compound may be only poorly soluble, it may be poorly transported across the mucosal epithelium, or it may have an undesirably short plasma half-life. Further discussion on pro-drugs may be found in Stella, V. J. et al, "Prodrugs", Drug Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp. 455-473.
  • a pro-drug form of a pharmacologically-active compound according to the inven- tion will generally be a compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an TV-oxide form thereof, or a quaternary ammonium salt thereof, having an acid group which is esterified or amidated. Included in such esterified acid groups are groups of the formula -COOR X , where R x is a C 1-6 alkyl, phenyl, benzyl or one of the following groups :
  • Amidated groups include groups of the formula - CONR y R z , wherein R y is H,
  • a compound according to the invention having an amino group may be derivatised with a ketone or an aldehyde such as formaldehyde to form a Mannich base. This base will hydrolyze with first order kinetics in aqueous solution.
  • stereochemically isomeric form defines all the possible stereochemically isomeric forms that a compound of Formula (I) may possess.
  • chemical designation of a compound denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all di- astereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration.
  • the configuration of the second stereogenic center is indicated using relative descriptors [R*,R* J or [R*,S*J, where R* is always specified as the reference center and [R*,R*] indicates centers with the same chirality and [i?*,5 * *] indicates centers of unlike chirality. For example, if the lowest-numbered chiral center in the molecule has an S configuration and the second center is R, the stereo descriptor would be specified as S-[R*, S*].
  • the position of the highest priority sub- stituent on the asymmetric carbon atom in the ring system having the lowest ring num- ber is arbitrarily always in the " ⁇ " position of the mean plane determined by the ring system.
  • the position of the highest priority substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in a compound according to Formula (I)) relative to the position of the highest priority substituent on the reference atom is denominated " ⁇ ", if it is on the same side of the mean plane determined by the ring system, or " ⁇ ", if it is on the other side of the mean plane determined by the ring system.
  • a compound according to the invention is inherently intended to comprise all isotopic combinations of its chemical elements.
  • a chemical element in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally occuring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • hydro- gen when hydro- gen is mentioned, it is understood to refer to 1 H, 2 H, 3 H and mixtures thereof ; when carbon is mentioned, it is understood to refer to 11 C, 12 C, 13 C, 14 C and mixtures thereof ; when nitrogen is mentioned, it is understood to refer to 13 N, 14 N, 15 N and mixtures thereof ; when oxygen is mentioned, it is understood to refer to 14 O, 15 O, 16 O, 17 O, 18 O and mixtures thereof ; and when fluor is mentioned, it is understood to refer to 18 F, 19 F and mixtures thereof.
  • a compound according to the invention therefore inherently comprises a compound with one or more isotopes of one or more element, and mixtures thereof, including a radioactive compound, also called radio labelled compound, wherein one or more non-radioactive atoms has been replaced by one of its radioactive isotopes.
  • radio labelled compound any compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an TV-oxide form thereof, or a quaternary ammonium salt thereof, which contains at least one radioactive atom.
  • a compound can be labelled with positron or with gamma emitting radioactive isotopes.
  • the 3 H-atom or the 125 I-atom is the atom of choice to be replaced.
  • PET positron emitting
  • the most commonly used positron emitting (PET) radioactive isotopes are 11 C, 18 F, 15 O and 13 N, all of which are accelerator produced and have half-lives of 20, 100, 2 and 10 minutes respectively. Since the half-lives of these radioactive isotopes are so short, it is only feasible to use them at institutions which have an accelerator on site for their production, thus limiting their use.
  • the most widely used of these are 18 F, 99m Tc, 201 Tl and 123 I.
  • the handling of these radioactive isotopes, their production, isolation and incorporation in a molecule are known to the skilled person.
  • the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen.
  • the radioactive atom is selected from the group of hydrogen, carbon and halogen.
  • the radioactive isotope is selected from the group of 3 H, 11 C, 18 F, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is se- lected from the group of ⁇ , 11/ C and 1 1 8T ⁇ .
  • a compound according to the invention can generally be prepared by a successive- sion of steps, each of which is known to the skilled person.
  • a pyridinone derivative can be prepared according to one or more of the following preparation methods.
  • the copper coupling reaction is performed in the presence of a copper salt, such as Cu(OAc) 2 , in an aprotic solvent such as 1 ,2-dichloromethane, in the presence of an amine and amine TV-oxide, such as pyridine and TEMPO, at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically overnight at room temperature.
  • a copper salt such as Cu(OAc) 2
  • an aprotic solvent such as 1 ,2-dichloromethane
  • an amine and amine TV-oxide such as pyridine and TEMPO
  • the pal- ladium coupling reaction is performed in an aprotic solvent such as toluene, in the presence of a palladium catalyst such as Pd(AcO) 2 , and in the presence of tBuOK, as a base, and a ligand, such as BINAP, at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically 24 hours at 100 0 C under traditional heating.
  • aprotic solvent such as toluene
  • a palladium catalyst such as Pd(AcO) 2
  • tBuOK as a base
  • a ligand such as BINAP
  • the copper coupling reaction is performed in the presence of a copper salt, such as CuI, in an aprotic solvent such as 1,4-dioxane, in the presence of an amine, such as ⁇ /, ⁇ -dimethylethylenediamine, in the presence of a base, such as potassium phospate, at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically 15 minutes at 180 0 C under microwave irradiation.
  • a copper salt such as CuI
  • an aprotic solvent such as 1,4-dioxane
  • an amine such as ⁇ /, ⁇ -dimethylethylenediamine
  • a base such as potassium phospate
  • the OH-activation can be done via trifiate, in the presence of a sulphonilating agent, such as N-phenyltrifluoromethanesulfonimide, in an aprotic solvent such as THF, in the presence of a base, such as potassium carbonate, at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically 15 minutes at 120 0 C under microwave irradiation.
  • a sulphonilating agent such as N-phenyltrifluoromethanesulfonimide
  • THF aprotic solvent
  • a base such as potassium carbonate
  • the palladium coupling reaction is performed in an aprotic solvent such as toluene or dioxane in the presence of a palladium catalyst such as Pd(AcO) 2 , or Pd(PPh 3 ⁇ and in the presence of a base, such as tBuOK or cessium carbonate, or inorganic aqueous base such as Na 2 CO 3 , and sometimes a ligand, such as BINAP or XANTPHOS, is required, at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically 24 hours at 100 0 C under traditional heating.
  • a palladium catalyst such as Pd(AcO) 2 , or Pd(PPh 3 ⁇
  • a base such as tBuOK or cessium carbonate
  • inorganic aqueous base such as Na 2 CO 3
  • a ligand such as BINAP or XANTPHOS
  • Hydrogenation is performed under hydrogen pressure, in a protic or aprotic solvent, such as EtOH, or EtOAc, in the presence of palladium as a catalyst.
  • Alkylation is performed in the presence of an organic or inorganic base, such as NaH, or DBU, in an aprotic solvent such as CH 3 CN, or DMF at a convenient temperature to completion of the reaction, typically 130 0 C for 30 minutes under microwave irradiation.
  • a Mitsun- obu type reaction can be performed in the presence of a phosphine, such as triphenyl- phosphine, an azodicarboxylate derivative, such as diethylazodicarboxilate in an aprotic solvent, such as THF, at a convenient temperature and time to completion of the reaction, such as 100 0 C for 5 minutes under microwave irradiation.
  • a phosphine such as triphenyl- phosphine
  • an azodicarboxylate derivative such as diethylazodicarboxilate
  • an aprotic solvent such as THF
  • Halogenation is per- formed with a suitable halogenating agent, such as POBr 3 , in a suitable solvent, such as DMF, at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically overnight at 100 0 C under traditional heating.
  • the palladium coupling reaction of boronic acids is performed in an aprotic solvent such as dioxane in the presence of a palladium catalyst such as Pd(PPh 3 )4 and in the presence of an inorganic aqueous base such as Na 2 CO 3 , at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically 10 minutes at 150 0 C under microwave heating.
  • an aprotic solvent such as dioxane
  • a palladium catalyst such as Pd(PPh 3 )4
  • an inorganic aqueous base such as Na 2 CO 3
  • the copper coupling reaction with boronic acids is performed in the presence of a copper salt, such as Cu(OAc) 2 , in an aprotic solvent such as 1 ,2-dichloromethane, in the presence of an amine and amine TV-oxide, such as pyridine and TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxy), at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically room temperature overnight.
  • the reduction in performed with an appropriate reducting agent, such as NaBH 4 , in the presence of a suitable solvent such as MeOH at room temperature for a period of time to ensure the completion of the reaction.
  • the palladium coupling with amines is performed in an aprotic solvent such as toluene or dioxane in the presence of a palladium catalyst such as Pd(AcO) 2 , or Pd(PPh 3 ) 4 and in the presence of a base, such as tBuOK or cessium carbonate, or inorganic aqueous base such as Na 2 CO 3 , and sometimes a ligand, such as BINAP or XANTPHOS, is required, at a convenient temperature, either by conventional heating or under microwave irradiation, for a period of time to ensure the completion of the reaction, typically 24 hours at 100 0 C under traditional heating.
  • amine substitution is preferably performed using an aprotic solvent, such as DMF, in the presence of the nucleophilic amine, and a base such as DIPEA or DBU, heating at a convenient temperature under traditional heating or microwave irradiation, for a period of time to ensure the completion of the reaction.
  • an aprotic solvent such as DMF
  • the copper coupling reaction is performed using an aprotic solvent, such as dioxane or DMF, in the presence of CuI, an inorganic base such K3PO4 and MeNH(CH ⁇ ) 2 NHMe as ligand, heating at a convenient temperature under traditional heating or microwave irradiation, for a period of time to ensure the completion of the reaction, typically 25 minutes at 175 0 C under microwave irradiation.
  • an aprotic solvent such as dioxane or DMF
  • a compound according to the invention in particular compounds according to
  • TV-oxide form thereof or a quaternary ammonium salt thereof have surprisingly been shown to have a binding affinity towards the MCH-receptor, in particular towards the MCH-I receptor, in particular as an antagonist.
  • a compound according to the invention are suitable for the prevention and/or treatment of diseases where antagonism of the
  • MCH-receptor in particular antagonism of the MCH-I receptor is of therapeutic use.
  • a compound according to the invention may be suitable for treatment and/or prophylaxis of psychiatric disorders, including but not limited to : anxiety, including but not limited to agoraphobia ; generalized anxiety ; compul- sion ; obsessive-compulsive disorder ; panic disorder ; social phobia ; and stress, such a post-traumatic stress ; attention def ⁇ cit/hyperactivity disorder ; autism ; - dysthymia ; eating disorder, including but not limited to anorexia ; binge eating ; and bulimia nervosa ; - impulse control disorder ; mental retardation, including but not limited to fragile X syndrome ; - mood disorder, including but not limited to agitation ; bipolar disorder, such as bipolar affective disorder, bipolar disorder (I), bipolar disorder (II), hypomania and mania ; depression, such as major depression and suicidal depression ; seasonal mood disorder ; and suicide ; premenstrual syndrome, including but not
  • a compound according to the invention may be used for treating sexual disorders, neurological disorders, and most in particular obesity and diabetes.
  • the invention therefore relates to a compound according to the general Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an TV-oxide form thereof or a quaternary ammonium salt thereof, for use as a medicine.
  • the invention also relates to the use of a compound according to the invention for the preparation of a medicament for the prevention and/or treatment of diseases where antagonism of the MCH-receptor, in particular antagonism of the MCH-I receptor is of therapeutic use.
  • the invention also relates to the use of a compound according to the invention for the preparation of a medicament for the prevention and/or treatment of anxiety, eating disorders, mood disorders, such as bipolar disorders and depression, psychoses, such as schizophrenia, and sleeping disorders. Additionally, a compound according to the invention may be used for treating sexual disorders and neurological disorders, and in particular obesity and diabetes.
  • the compounds according to the invention, in particular according to Formula (I) may be co-administered as add-on treatment and/or prophylaxis in the above listed diseases.
  • antidepressants anxiolytics and/or antipsychotics.
  • the compounds according to the invention in particular according to Formula (I) may be co-administered in combination with antidepressants, anxiolytics and/or antipsychotics which are currently available or in development or which will become available in the future, in particular to improve efficacy and/or onset of action.
  • antidepressants anxiolytics and/or antipsychotics which are currently available or in development or which will become available in the future, in particular to improve efficacy and/or onset of action.
  • the compounds of the present invention and the other agents may be present as a combined preparation for simultaneous, separate or sequential use for the prevention and/or treatment of depression and/or anxiety. Such combined preparations may be, for example, in the form of a twin pack.
  • the compounds of the present invention and the other agents may be administered as separate pharmaceutical compositions, either simultaneously or sequentially.
  • the invention therefore relates to a pharmaceutical composition according to the invention, characterized in that is comprises further one or more other compounds se- lected from the group of antidepressants, anxiolytics and antipsychotics.
  • Suitable classes of antidepressant agents include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRTs), monoamine oxidase inhibitors (MAOI's), reversible inhibitors of monoamine oxidase (RIMA's), serotonin and noradrenaline reuptake inhibitors (SNRTs), noradrenergic and specific serotonergic an- tidepressants (NaSSA's), corticotropin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists and atypical antidepressants.
  • SSRTs selective serotonin reuptake inhibitors
  • MAOI's monoamine oxidase inhibitors
  • RIMA's reversible inhibitors of monoamine oxidase
  • SNRTs noradrenergic and specific serotonergic an- tidepressants
  • CRF corticotropin releasing factor
  • norepinephrine reuptake inhibitors include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, amoxapine, desipramine, maprotiline, nortriptyline, protriptyline, reboxetine and pharmaceutically acceptable salts thereof.
  • Suitable examples of selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine, sertraline and pharmaceutically acceptable salts thereof.
  • Suitable examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, tranylcypromine, selegiline and pharmaceutically acceptable salts thereof.
  • Suitable examples of reversible inhibitors of monoamine oxidase include mo- clobemide and pharmaceutically acceptable salts thereof.
  • Suitable examples of serotonin and noradrenaline reuptake inhibitors include venlafaxine and pharmaceutically acceptable salts thereof.
  • Suitable atypical antidepressants include bupropion, lithium, nefazodone, trazodone, viloxazine, sibutramine and pharmaceutically acceptable salts thereof.
  • Other suitable antidepressants include adinazolam, alaproclate, amineptine, amitriptyline/chlordiazepoxide combination, atipamezole, azamianserin, apelinaprine, befuraline, bifemelane, binodaline, bipenamol, brofaromine, bupropion, caroxazone, cericlamine, cianopramine, cimoxatone, citalopram, clemeprol, clovoxamine, dazepinil, deanol, demexiptiline, dibenzepin, dothiepin, droxidopa, enefexine, estazolam, etoperi- done, femoxetine, feng
  • Suitable classes of anti-anxiety agents include benzodiazepines and 5-HT IA recep- tor agonists or antagonists, especially 5-HT IA partial agonists, corticotropin releasing factor (CRF) antagonists, compounds having muscarinic cholinergic activity and com- pounds acting on ion channels.
  • benzodiazepines other suitable classes of anti-anxiety agents are nonbenzodiazepine sedative-hypnotic drugxs such as Zolpidem; mood-stabilizing drugs such as clobazam, gabapentin, lamotrigine, loreclezole, oxcar- bamazepine, stiripentol and vigabatrin; and barbiturates.
  • Suitable antipsychotic agents are selected from the group consisting of aceto- phenazine, in particular the maleate salt; alentemol, in particular the hydrobromide salt; alpertine; azaperone; batelapine, in particular the maleate salt; benperidol; benzin- dopyrine, in particular the hydrochloride salt; brofoxine; bromperidol; butaclamol, in particular the hydrochloride salt; butaperazine; carphenazine, in particular the maleate salt; carvotroline, in particular the hydrochloride salt; chlorpromazine; chlorprothixene; cinperene; cintriamide; clomacran, in particular the phosphate salt; clopenthixol; clopi- mozide; clopipazan, in particular the mesylate salt; cloroperone, in particular the hydrochloride salt; clothiapine; clothixamide, in particular the maleate salt; cloza
  • the compounds according to the invention, in particular according to Formula (I) may also be used in conjunction with other lipid-lowering agent, thus leading to a so-called combination lipid-lowering therapy for the treatment of obesity.
  • the said ad- ditional lipid-lowering agent may be, for instance, a known drug conventionally used for the management of hyperlipidaemia such as e.g. a bile acid sequestrant resin, a fi- bric acid derivative or nicotinic acid as previously mentioned in the background of the invention.
  • Suitable additional lipid-lowering agents also include other cholesterol biosynthesis inhibitors and cholesterol absorption inhibitors, especially HMG-CoA reduc- tase inhibitors and HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, CETP inhibitors, ACAT inhibitors, squalene synthetase inhibitors, CB-I antagonists, cholesterol absorption inhibitors such as ezetimibe, and the like.
  • HMG-CoA reductase inhibi- tor refers to a compound which inhibits the biotransformation of hydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by the enzyme HMG-CoA reductase.
  • HMG-CoA reductase inhibitors are, for example, lovastatin, simvastatin, fiuvastatin, pravastatin, rivastatin, and atorvastatin.
  • HMG-CoA synthase inhibitor refers to a compound which inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoace- tyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase
  • HMG-CoA reductase gene expression inhibitor may be used as the second compound in the combination therapy aspect of this invention.
  • These agents may be HMG-CoA reductase trancription inhibitors that block the transcription of DNA or translation inhibitors that prevent translation of mRNA coding for HMG-CoA reductase into protein.
  • Such inhibitors may either affect trancription or translation directly or may be biotransformed into compounds having the above-mentioned attributes by one or more enzymes in the cholesterol biosynthetic cascade or may lead to accumulation of a metabolite having the above-mentioned activities.
  • CETP inhibitor refers to a compound which inhibits the cholesteryl ester transfer protein (CETP) mediated transport of various cholesteryl esters and triglycerides from HDL to LDL and VLDL.
  • ACAT inhibitor refers to a compound which inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl CoAxholesterol acyltransferase.
  • squalene synthetase inhibitor refers to a compound which inhibits the condensation of two molecules of farnesylpyrophosphate to form squalene, catalyzed by the enzyme squalene synthetase.
  • compositions also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, an TV-oxide form thereof or a quaternary ammonium salt thereof.
  • a compound according to the invention in particular a compound according to Formula (I)
  • Formula (I), the pharmaceutically acceptable acid or base addition salt thereof, an TV-oxide form thereof or a quaternary ammonium salt thereof , or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • compositions of this invention an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • In- jectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof. Since the compounds ac- cording to the invention are potent orally administrable dopamine antagonists, pharmaceutical compositions comprising said compounds for administration orally are especially advantageous.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention and one or more other compounds selected from the group of antidepressants, anxiolytics, antipsychotics and lipid- lowering agents as well as to the use of such a composition for the manufacture of a medicament.
  • weight ratio of the compounds according to the invention to the one or more other compounds may be in the range of 0.05/0.94 to 0.94/0.05, more in particular 0.10/0.89 to 0.89/0.10, and any number therein between.
  • THF tetrahydrofuran
  • DMF means 7V,7V-dimethyl- formamide
  • EtOAc means ethyl acetate
  • DCM means dichloromethane
  • DME means 1,2-dimethoxyethane
  • DCE means 1 ,2-dichloroethane
  • DIPE means diiso- propylether
  • DMSO means dimethylsulfoxide
  • boc means tert-butoxy carbonyl
  • Cu(OAc) 2 means copper acetate
  • BINAP is l,l'-[l,l'-binaphthalene]- 2,2'-diylbis[l,l]diphenyl-phosphine
  • DBU means l,8-diaza-7-bicyclo[5.4.0]- undecene
  • DIPEA means N-ethyl-N-(l-methylethyl)-2-prop
  • Microwave assisted reactions were performed in a single-mode reactor: Initia- torTM Sixty EXP microwave reactor (Biotage AB). Description of the instrument can be found in www.biotage.com. And in a multimode reactor: MicroSYNTH Labstation
  • intermediate compound 1-2 (0.760 g, 3.3 mmol), potassium carbonate (1.38 g, 10 mmol) in THF, N-phenyltrifluoromethanesulphonimide (1.18 g, 3.3 mmol) was added.
  • the reaction heated in a microwave oven for 15 minutes at 120 0 C. Then, the solid was filtered off and washed with DCM. The filtrate solvent was evaporated and the residue was purified by column chromatography over silica gel (eluent: DCM, DCMiEtOAc 9/1 and 4/1). The product fractions were collected and the solvent was evaporated. The residue was treated with DIPE to yield intermediate compound 1-3 (0.900 g, 60 %).
  • Tables Ia, 2, 3a, 4 and 5 list the compounds of Formula (I), which were prepared according to one of the above described examples.
  • Example “Ex. Nr.” the examples that are described in detail in the experimental section above, have been marked with "*”.
  • the analytical data for the compounds, measured according to one or more of the analytical procedures described below, are also present in these tables.
  • Tables Ib and 3b list the compounds of Formula (I), which are prepared according to one of the above described examples.
  • the HPLC gradient was supplied by a HP 1100 from Agilent Technologies comprising a pump (quaternary or binary) with degasser, an autosampler, a column oven, a diode-array detector (DAD) and a column as specified in the respective methods below.
  • Flow from the column was split to a MS spectrometer.
  • the MS detector was configured with an electrospray ionization source. Nitrogen was used as the nebulizer gas.
  • the source temperature was maintained at 140 °C. Data acquisition was performed with MassLynx-Openlynx software.
  • LCMS general procedure B The HPLC gradient was supplied by an Alliance HT 2790 (Waters) system comprising a quaternary pump with degasser, an autosampler, a column oven (set at 40 0 C), a diode-array detector (DAD) and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 1 second using a dwell time of 0.1 second. The capillary needle voltage was 3 kV and the source temperature was maintained at 140 0 C. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.
  • LCMS method 1 In addition to general procedure A: Reversed phase HPLC was carried out on an ACE-C 18 column (3.0 ⁇ m, 4.6 x 30 mm) from Advanced Chromatography Technologies, with a flow rate of 1.5 ml/min, at 4O 0 C.
  • the gradient conditions used are: 80 % A (0.5 g/1 ammonium acetate solution), 10 % B (acetonitrile), 10 % C (methanol) to 50 % B and 50 % C in 6.5 minutes, to 100 % B at 7 minutes and equilibrated to initial conditions at 7.5 minutes until 9.0 minutes. Injection volume 5 ⁇ l.
  • High-resolution mass spectra (Time of Flight, TOF) were acquired only in positive ionization mode by scanning from 100 to 750 in 0.5 seconds using a dwell time of 0.1 seconds.
  • the capillary needle voltage was 2.5 kV for positive ionization mode and the cone voltage was 20 V.
  • Leucine-Enkephaline was the standard substance used for the lock mass calibration.
  • Reversed phase HPLC was carried out on an ACE-C 18 column (3.0 ⁇ m, 4.6 x 30 mm) from Advanced Chromatography Technologies, with a flow rate of 1.5 ml/min, at 4O 0 C.
  • the gradient conditions used are: 80 % A (0.5 g/1 ammonium acetate solution), 10 % B (acetonitrile), 10 % C (methanol) to 50 % B and 50 % C in 6.5 minutes, to 100 % B at 7 minutes and equilibrated to initial conditions at 7.5 minutes until 9.0 minutes. Injection volume 5 ⁇ l.
  • Reversed phase HPLC was carried out on a Chromolith (4.6 x 25 mm) with a flow rate of 3 ml/min.
  • Three mobile phases (mobile phase A: 95 % 25 mM ammoniumacetate + 5 % acetonitrile; mobile phase B: acetoni- trile; mobile phase C: methanol) were employed to run a gradient condition from 96 % A, 2 % B and 2 % C, to 2 % A, 49 % B and 49 % C in 0.9 minutes, to 100 % B in 0.3 minutes and hold for 0.2 minutes.
  • An injection volume of 2 ⁇ l was used.
  • Cone voltage was 10 V for positive ionization mode and 20 V for negative ionization mode.
  • melting points were determined in open capillary tubes on a Mettler FP62 apparatus. Melting points were measured with a temperature gradient of 3 or 10 °C/minute. Maximum temperature was 300 0 C. The melting point was read from a digital display.
  • MCH-I receptors The interaction of the compounds of Formula (I) with MCH-I receptors was assessed in in vitro transient calcium (Ca 2+ ) mobilization assays in the fiuorimetric imaging plate reader (FLIPR) format (Sullivan et al. 1999, Methods MoI Biol 114:125-133).
  • FLIPR fiuorimetric imaging plate reader
  • MCH natural agonist
  • the interaction of the test compounds with the receptor is assessed in competition experiments.
  • concentrations of the test compound are added to the incubation mixture containing the receptor-expressing cells and a submaximal concentra- tion of MCH.
  • the test compound in proportion to its antagonist potency and its concentration inhibits MCH-induced Ca 2+ mobilization.
  • Example Cl Binding Experiment for MCH-I Cell culture and membrane preparation.
  • Chinese Hamster ovary cells (CHO) stably expressing the human MCH-I receptor are grown in a 1:1 mixture of Dulbecco's Modified Eagles Medium (DMEM) and HAM's F 12 medium including GlutamaxTM (Invitrogen), supplemented with 10 % heat-inactivated fetal bovine serum and 400 ⁇ g/ml geneticin.
  • DMEM Dulbecco's Modified Eagles Medium
  • GlutamaxTM Invitrogen
  • MCH-I receptor-expressing CHO cells are seeded in 20 ⁇ l (5,000 cells per well) into 384-well black wall, clear bottom microtiter plates (Costar).
  • 20 ⁇ l per well calcium assay kit containing 10 mM probenicide (Molecular Devices) is added. Cells are loaded for 90 min at 37 °C and 5 % CO 2 in a cell culture incubator. After loading, 20 ⁇ l of serial dilutions of the test compound are added and cells are further incubated for 20 min at room temperature in the dark. After 20 min, 20 ⁇ l of a submaximal MCH concentration is added and changes in intracellular calcium are recorded directly in a FLIPR III apparatus (Molecular devices).
  • All compounds according to Formula (I) produced an inhibition of more than 50 % (pICso) at a test concentration ranging between 10 "6 M and 10 "9 M in a concentration-dependent manner.
  • Example C.2 Determination of brain concentrations
  • the dosing formulations were prepared by individually dissolving the compounds in a 10 % hydroxypropyl- ⁇ -cyclodextrin (HP- ⁇ -CD) solution at a final concentration of 1.25 mg/ml for the IV-formulations and they were made isotonic with manni- tol.
  • the formulations were stored at room temperature, protected from light and were analysed quantitatively with LC-MS/MS on the day of preparation. The stability of these formulations was checked on the day of dosing. Dose administration was done intravenously in a tail vein at 2 ml/kg to obtain a dose of 2.5 mg/kg.
  • Sample time points were 1 and 4 h after intravenous dose administration. Animals were sacrificed by decapitation and blood was collected by exsanguination in 10 ml B-D Sterile EDTA K3 Vacutainer tubes. From each individual animal the whole brain was dissected and weighed. Individual brain samples were homogenized in demineralized water (1/9 w/v or + 3 ml if tissue weight ⁇ 0.33 g). Homogenisation was carried out under dimmed light conditions. The brain samples were analysed using a qualified research LC-MS/MS method. The lower limit of quantification (LLOQ) was in the range of 20 - 50 ng/g.
  • LLOQ lower limit of quantification
  • Table 7 Comparison of brain levels.
  • Active ingredient (a.i.) as used throughout these examples relates to a final compound of formula (i), the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the TV-oxide form thereof, a quaternary ammonium salt thereof and prodrugs thereof.
  • Example D.I oral drops
  • Example D.2 oral solution
  • Example D.3 film-coated tablets Preparation of . tablet . . core A mixture of 100 grams of the a.L, 570 grams lactose and 200 grams starch is mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture is sieved, dried and sieved again. Then there is added 100 grams micro crystalline cellulose and 15 grams hydrogenated vegetable oil. The whole is mixed well and com- pressed into tablets, giving 10,000 tablets, each containing 10 mg of the active ingredient.
  • Example D .4 injectable solution

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Abstract

La présente invention concerne des dérivés de pyridinone substituée par N-aryle et N-hétéroaryle présentant une activité antagoniste de l'hormone de mélano-concentration (MCH), en particulier l'activité de MCH-1, représentés par la formule générale (I), un sel d'addition acide ou d'addition basique pharmaceutiquement acceptable desdits dérivés, une forme N-oxyde de ceux-ci ou un sel d'ammonium quaternaire de ceux-ci, les variables étant définies dans la revendication 1. Elle concerne en outre leur préparation, des compositions les comprenant et leur utilisation comme médicament. Les composés selon l'invention sont utiles pour la prévention et/ou le traitement de troubles psychiatriques, comprenant, mais sans y être limités, l'anxiété, les troubles de l'alimentation, les troubles de l'humeur, tels que les troubles bipolaires et la dépression, les psychoses, telles que la schizophrénie, et les troubles du sommeil; l'obésité; le diabète; les troubles sexuels et les troubles neurologiques.
PCT/EP2007/055376 2006-06-02 2007-06-01 Nouveaux dérivés de pyridinone substituée par n-aryle et n-hétéroaryle en vue d'une utilisation dans des maladies à médiation par mch-1 WO2007141200A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP06114917.5 2006-06-02
EP06114917 2006-06-02
EP06123263 2006-10-31
EP06123263.3 2006-10-31

Publications (2)

Publication Number Publication Date
WO2007141200A1 true WO2007141200A1 (fr) 2007-12-13
WO2007141200A8 WO2007141200A8 (fr) 2008-03-27

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WO2008041090A1 (fr) * 2006-10-06 2008-04-10 Pfizer Limited Pyridinones antagonistes du récepteur 1 de l'hormone de concentration de la mélanine
WO2009089482A1 (fr) 2008-01-11 2009-07-16 Albany Molecular Research, Inc. Pyridoindoles (1-azinone)-substitués en tant qu'antagonistes mch
WO2010104818A1 (fr) * 2009-03-09 2010-09-16 Bristol-Myers Squibb Company Analogues d'azapyridone utiles comme antagonistes du récepteur 1 de l'hormone concentrant la mélanine
WO2010141539A1 (fr) * 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones en tant qu'antagonistes du recepteur 1 de l'hormone de melano-concentration
WO2010141545A1 (fr) * 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones à usage d'antagonistes de récepteur d'hormone concentrant la mélanine 1
WO2011003005A1 (fr) * 2009-07-01 2011-01-06 Albany Molecular Research, Inc. Antagonistes de mch-1 d’azépino[b]indole et pyrido-pyrrolo-azépine azinone-substitué, procédés de préparation, et utilisation de ceux-ci
WO2011127643A1 (fr) * 2010-04-12 2011-10-20 Merck Sharp & Dohme Corp. Dérivés de pyridone
US20120316200A1 (en) * 2010-04-12 2012-12-13 Merck Sharp & Dohme Corp. Pyridone derivatives
WO2013149362A1 (fr) * 2012-04-06 2013-10-10 Glaxosmithkline Llc 1-(dihydronaphtalényl)pyridones en tant qu'antagonistes du récepteur 1 de l'hormone de concentration de la mélanine
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US9115089B2 (en) 2013-06-07 2015-08-25 Confluence Life Sciences, Inc. Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9359300B2 (en) 2010-12-06 2016-06-07 Confluence Life Sciences, Inc. Methyl/difluorophenyl-methoxy substituted pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds, and methyl-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9365546B2 (en) 2010-12-06 2016-06-14 Confluence Life Sciences Inc. Substituted pyridinone-pyridinyl compounds
US9434695B2 (en) 2012-07-18 2016-09-06 Sunshine Lake Pharma Co., Ltd Nitrogenous heterocyclic derivatives and their application in drugs
US9902712B2 (en) 2013-12-19 2018-02-27 Sunshine Lake Pharma Co., Ltd. Nitrogenous heterocyclic derivatives and their application in drugs
JP2019524811A (ja) * 2016-08-08 2019-09-05 ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド ヒドロニドンの製造方法
JP2019525946A (ja) * 2016-08-08 2019-09-12 ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド ヒドロニドンの製造方法
EP4151210A3 (fr) * 2020-01-10 2023-06-14 Harmony Biosciences, LLC Derives de la pyrdine-carboline en tant qu'antagonistes de mchr1 pour leur utilisation en therapie
US11844801B2 (en) 2020-03-27 2023-12-19 Aclaris Therapeutics, Inc. Oral compositions of MK2 pathway inhibitor for treatment of immune conditions

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008041090A1 (fr) * 2006-10-06 2008-04-10 Pfizer Limited Pyridinones antagonistes du récepteur 1 de l'hormone de concentration de la mélanine
US9296743B2 (en) 2008-01-11 2016-03-29 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
WO2009089482A1 (fr) 2008-01-11 2009-07-16 Albany Molecular Research, Inc. Pyridoindoles (1-azinone)-substitués en tant qu'antagonistes mch
AU2009204048B2 (en) * 2008-01-11 2013-08-01 Albany Molecular Research, Inc. (1-azinone) -substituted pyridoindoles as MCH antagonists
US8716308B2 (en) 2008-01-11 2014-05-06 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
JP2014129417A (ja) * 2008-01-11 2014-07-10 Albany Molecular Research Inc Ｍｃｈ拮抗薬としての（１−アジノン）置換ピリドインドール類
US9650378B2 (en) 2008-01-11 2017-05-16 Albany Molecular Research, Inc. (1-azinone)-substituted pyridoindoles
JP2011509937A (ja) * 2008-01-11 2011-03-31 アルバニー モレキュラー リサーチ， インコーポレイテッド Ｍｃｈ拮抗薬としての（１−アジノン）置換ピリドインドール類
KR101614723B1 (ko) 2008-01-11 2016-04-22 알바니 몰레큘라 리써치, 인크. Ｍｃｈ 길항물질로서 (1-아지논)-치환된 피리도인돌
EP2476680A1 (fr) * 2008-01-11 2012-07-18 Albany Molecular Research, Inc. Pyridoindoles à substitution (1-azinone)
US8278316B2 (en) 2009-03-09 2012-10-02 Bristol-Myers Squibb Company Aza pyridone analogs useful as melanin concentrating hormone receptor-1 antagonists
WO2010104818A1 (fr) * 2009-03-09 2010-09-16 Bristol-Myers Squibb Company Analogues d'azapyridone utiles comme antagonistes du récepteur 1 de l'hormone concentrant la mélanine
WO2010141545A1 (fr) * 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones à usage d'antagonistes de récepteur d'hormone concentrant la mélanine 1
WO2010141539A1 (fr) * 2009-06-03 2010-12-09 Glaxosmithkline Llc Bis-pyridylpyridones en tant qu'antagonistes du recepteur 1 de l'hormone de melano-concentration
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
WO2011003005A1 (fr) * 2009-07-01 2011-01-06 Albany Molecular Research, Inc. Antagonistes de mch-1 d’azépino[b]indole et pyrido-pyrrolo-azépine azinone-substitué, procédés de préparation, et utilisation de ceux-ci
JP2012532144A (ja) * 2009-07-01 2012-12-13 アルバニー モレキュラー リサーチ， インコーポレイテッド アジノン置換アゼピノ［ｂ］インドールおよびピリド−ピロロ−アゼピンｍｃｈ−１拮抗薬、ならびにその作製方法および使用
EP2558094A1 (fr) * 2010-04-12 2013-02-20 Merck Sharp & Dohme Corp. Dérivés de pyridone
EP2558094A4 (fr) * 2010-04-12 2013-09-25 Merck Sharp & Dohme Dérivés de pyridone
US20120316200A1 (en) * 2010-04-12 2012-12-13 Merck Sharp & Dohme Corp. Pyridone derivatives
WO2011127643A1 (fr) * 2010-04-12 2011-10-20 Merck Sharp & Dohme Corp. Dérivés de pyridone
US9359300B2 (en) 2010-12-06 2016-06-07 Confluence Life Sciences, Inc. Methyl/difluorophenyl-methoxy substituted pyridinone-pyridinyl compounds, methyl-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds, and methyl-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9365547B2 (en) 2010-12-06 2016-06-14 Confluence Life Sciences Inc. Substituted pyridinone-pyridinyl compounds
US9365546B2 (en) 2010-12-06 2016-06-14 Confluence Life Sciences Inc. Substituted pyridinone-pyridinyl compounds
US8697700B2 (en) 2010-12-21 2014-04-15 Albany Molecular Research, Inc. Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof
US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
WO2013149362A1 (fr) * 2012-04-06 2013-10-10 Glaxosmithkline Llc 1-(dihydronaphtalényl)pyridones en tant qu'antagonistes du récepteur 1 de l'hormone de concentration de la mélanine
US9434695B2 (en) 2012-07-18 2016-09-06 Sunshine Lake Pharma Co., Ltd Nitrogenous heterocyclic derivatives and their application in drugs
US9115089B2 (en) 2013-06-07 2015-08-25 Confluence Life Sciences, Inc. Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9636333B2 (en) 2013-06-07 2017-05-02 Confluence Life Sciences, Inc. Methyl/fluoro-pyridinyl-methoxy substituted pyridinone-pyridinyl compounds and fluoro-pyrimidinyl-methoxy substituted pyridinone-pyridinyl compounds
US9902712B2 (en) 2013-12-19 2018-02-27 Sunshine Lake Pharma Co., Ltd. Nitrogenous heterocyclic derivatives and their application in drugs
JP2019524811A (ja) * 2016-08-08 2019-09-05 ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド ヒドロニドンの製造方法
JP2019525946A (ja) * 2016-08-08 2019-09-12 ジーエヌアイ−イーピーエス ファーマシューティカルズ インコーポレイテッド ヒドロニドンの製造方法
EP4151210A3 (fr) * 2020-01-10 2023-06-14 Harmony Biosciences, LLC Derives de la pyrdine-carboline en tant qu'antagonistes de mchr1 pour leur utilisation en therapie
US11844801B2 (en) 2020-03-27 2023-12-19 Aclaris Therapeutics, Inc. Oral compositions of MK2 pathway inhibitor for treatment of immune conditions

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UY30378A1 (es) 2008-01-02
AR061163A1 (es) 2008-08-06
PE20080150A1 (es) 2008-04-11
TW200811146A (en) 2008-03-01
WO2007141200A8 (fr) 2008-03-27

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